Each of our cells contains our entire genetic heritage: 46 chromosomes inherited from our parents on which there are approximately 25,000 genes.
But if all our cells contain the same information, they obviously do not all make the same use of it: a skin cell does not resemble a neuron in any way, a cell of the liver does not have the same functions as a muscle cell.
Similarly, two twins who share the same genome are never perfectly identical. In these examples and in many others, the key to the mystery is called “epigenetics”.
Epigenetics corresponds to the field focusing on all the modifications (or factors) which are not encoded by the DNA sequence (methylations, prions, etc.). It regulates the activity of genes by facilitating or preventing their expression.
It is fundamental because it allows a different reading of the same genetic code. It explains, for example, the differences existing in identical twins.
Epigenetic processes
Three epigenetic processes of modification of gene expression are described here.
The first, DNA methylation, is the most studied in mammals.
DNA methylation is a change in the structure of DNA. It adds methylation groups to DNA, which depending on their location on the DNA sequence, can alter gene expression, i.e. the amount of messenger RNA (mRNA) produced by genes.
Gene regulation is also an important phenomenon in determining which genes are expressed (i.e. when and where) during the development of an organism. Scientists have recently discovered that DNA methylation is reversible.
At the time of fertilisation, the oocyte and the sperm show drastically different methylation profiles in mammals, which creates a methylation asymmetry on the paternal and maternal chromosomes in the newly formed embryo.
During the first days of development, these parental methylation profiles are reprogrammed. However, a handful of genes retain this parental methylation asymmetry throughout life, leading to their expression from a single chromosomal copy. Although few in number (about a hundred), the genes subjected to imprinting have a decisive role in foetal, neuronal and metabolic development.
The second process is histone modification.
Histones are proteins that serve to wind strands of DNA into groups of units, like beads on a necklace. Reversible chemical marks can modify specific sections of histones, resulting in the unfolding of packed DNA, which facilitates gene transcription and expression, or the condensation of DNA, which complicates their transcription and expression.
Researchers recently proposed a theory about the “histone language”, where different combinations of histone modifications would dictate certain processes associated with storing and recalling memories and would be responsible for behaviours linked to cognitive deficits, schizophrenia and depression.
In addition, recent studies have demonstrated the ability to reverse brain changes due to histone modification of a specific gene known to be associated with chronic drug-induced stress (an antidepressant).
A third newly discovered epigenetic process involves small non-coding RNA (ncRNA) that interferes with the expression of specific genes by promoting DNA compaction or causing the degradation of transcribed mRNA.
mRNA molecules carry instructions “etched” onto DNA to synthesise proteins. ncRNA molecules have been shown to be present in large amounts in the brain and ncRNA and mRNA interference has unravelled a fundamental principle of gene expression regulation . Epigenetic processes of ncRNA marking have been associated with several cognitive and behavioural disorders.
Where could the modifications come from?
Environmental impact
In 1944, during the Dutch hunger famine, the west part of Netherland suffered from famine because of a blocus decreed by Nazi Germany. Studies have shown that the children of women who suffered from this famine were more likely to be touched by troubles such as obesity, diabetes or heart failures and that they were small.
These data suggest that the famine endured by the mothers had provoked epigenetic modifications transmitted to following generations. The modification of the size comes from changes of epigenetic markers on DNA, directly linked to the deficiency of crucial molecules during the in-utero life.
To maintain a good level of methylation during cell division, new methyl groups must be added to newly copied DNA, but this constant inflow in methyl groups directly comes from the food eaten (amino acid and vitamins like methionine, betaine or choline).
Moreover, individuals that endure famine in utero have less methyl groups attached to the gene that codes for the production of a growth factor (insulin-like growth factor-2).
Stress
Chronic stress, the most frequently reported component in quality of life surveys, leads to changes in the neuronal structures of various elements of the limbic system (hippocampus, amygdala, prefrontal cortex).
This so-called maladaptive plasticity can result, in certain circumstances, in attention, memory and cognitive performance disorders.
The loss of adaptive capacities to chronic stress is also materialised by physical symptoms (pain, intestinal disorders, headaches), emotional (anxiety, apathy, depression, fatigue) and behavioural (sadness, aggressiveness, sleep disorders or ‘use).
Neuroglial mapping is therefore completely disrupted, characterised by a decrease in the expression of cortisol receptors and GABA receptors of neurons of the paraventricular nucleus (NPV) of the hypothalamus, a loss of capacity for neurogenesis, neuroinflammation and elements of mitochondrial dysfunction with oxidative stress.
In stressed individuals like battered children and victims of traumatic events, methylation of DNA is perturbed in specific genomic regions of the brain.
For example autopsies folowing the suicide of individuals abused or not in their childhood have shown epigenetic differences associated with this abuse: two cytosines were hypermethyled in the hippocampus of the abused individual.
Drug addiction
In terms of addictions, often of a compensatory nature, let us emphasise the key role of the opioid system in the central nervous system, regulating the perception of pain, the feeling of well-being and pleasure, and mood.
In recent years, in the face of soaring exposure to opiates, researchers have confirmed that their use causes long-term changes in brain regions involved in reward processing and motivation.
The mechanisms of this persistent remodelling are the result of epigenetic processes of gene expression programs in certain brain regions.
Current evidence indicates that opioids promote higher levels of permissive histone acetylation and lower levels of repressive histone methylation, as well as alterations in DNA methylation patterns and non-RNA expression.
Answers
From the assessments and measures relating to the quality of life, it appears that the management of chronic stress and its individual feelings (according to early determinism) as well as the reduction of addictive behaviours are important axes in order to “redesign” in terms of epigenetics a “positive” cartography of our health.
Epigenetic marks are reversible and so it could be possible to change the marks that induce diseases. Some medicines directly act on epigenetic mechanisms to eliminate abnormal marks: this is epidrugs or epimedicines. Two types of it have been created; one that disables DNA methylation and one that focuses on histone modification.
The constant improvement of our understanding of the human body mechanics, through epigenetics as well, increases the number of ways by which we can modify and enhance it.
